In:
Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 77, No. 3 ( 2023-03), p. 745-759
Abstract:
IL‐10‐producing regulatory B cells (IL‐10 + B cells), a dominant regulatory B cell (Breg) subset, foster tumor progression. However, the mechanisms underlying their generation in HCC are poorly understood. Ten‐eleven translocation‐2 (TET2), a predominant epigenetic regulatory enzyme in B cells, regulates gene expression by catalyzing demethylation of 5‐methylcytosine into 5‐hydroxymethyl cytosine (5hmC). In this study, we investigated the role of TET2 in IL‐10 + B cell generation in HCC and its prospects for clinical application. Approach and Results: TET2 activation in B cells triggered by oxidative stress from the HCC microenvironment promoted IL‐10 expression, whereas adoptive transfer of Tet2 ‐deficient B cells suppressed HCC progression. The aryl hydrocarbon receptor is required for TET2 to hydroxylate Il10 . In addition, high levels of IL‐10, TET2, and 5hmc in B cells indicate poor prognosis in patients with HCC. Moreover, we determined TET2 activity using 5hmc in B cells to evaluate the efficacy of anti‐programmed death 1 (anti‐PD‐1) therapy. Notably, TET2 inhibition in B cells facilitates antitumor immunity to improve anti‐PD‐1 therapy for HCC. Conclusions: Our findings propose a TET2‐dependent epigenetic intervention targeting IL‐10 + B cell generation during HCC progression and identify the inhibition of TET2 activity as a promising combination therapy with immune checkpoint inhibitors for HCC.
Type of Medium:
Online Resource
ISSN:
0270-9139
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2023
detail.hit.zdb_id:
1472120-X
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